Factory & Hospital hygiene, Chap 21(7 th edition) Principles of GMP, Chap 23 (8 th edition ) (Hugo & Russel s Pharmaceutical microbiology) Dr Randa Haddadin ١
Quality: means fitness for purpose, i.e product is not only effective but also safe for the route of administration intended QA: Wide range concept covering all matters which influence the quality of product. It is the total sum of procedures needed to ensure the fitness of pharmaceutical product for its intended use ٢
Good manufacturing practice GMP: part of QA, which aimed at ensuring the product is consistently manufactured to a quality appropriate for its intended use & meets the requirements of regulatory authorities. It involves personnel, premises & equipment, materials, procedures, documents & records. QC: part of GMP. Concerned with sampling, specifications, testing, documentation & release procedures In-process control: any test on product, environment or equipment during the manufacturing process Control of microbial contamination during manufacture: To reduce the risk of contamination several measures can be taken: 1. Risk assessment by Hazard analysis of critical control points (HACCP): is a tool for evaluating steps in manufacturing process which involves analysis & identification of potential hazard or risk of each step, what are the critical points, establishing of critical limits & system to monitor the critical points, corrective measures to be taken, verify that HACCP is effective, documentation ٣
2. Environmental cleanliness & hygiene all premises, including processing areas, stores and laboratories, should be maintained in a clean, dry and tidy condition. For easy cleaning, walls, floors and ceilings should have washable & impervious surfaces, and floors should be free from cracks and open joints where microorganisms could be harboured. Also coving should be used at the junction between walls and floors or ceilings. Procedures for cleaning and disinfection of premises are required and must be enforced. All equipment involved in the manufacturing process should be easy to dismantle and clean. 'clean' air should be supplied during manufacturing processes. High standards of personal hygiene are therefore very important (free from communicable diseases, no open lesions), hand disinfection facilities, protective garments, headgear, gloves as direct contact with the product is not allowed Staff should be trained in the principles of GMP &basic training ٤ in microbiology
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3. Quality of starting materials (active, inactive & water) Materials of natural origin are usually associated with an extensive microbial flora and require careful storage to prevent growth of the organisms and spoilage of the material. If stable, natural products with a high microbial count may undergo sterilization before use. 4. Process design The manufacturing process must be fully defined and capable of yielding, with the facilities available, a product that is microbiologically acceptable and conforms to its specifications. 5.Quality control and documentation QC should set acceptable microbiology standards all raw materials, together with microbial limits for in-process samples and the final product. also there should be validation of cleaning & disinfection & monitoring of production environment. All of these aspects must be documented. 6. Packaging, storage and transport The product is contained in primary package then placed inside secondary packaging (packs, cartons, boxes). Consideration must be given to the fabric of the package & its cleaning & the actual process of packaging. ٦
Manufacture of sterile products Sterile products are either terminally sterilized or can not be terminally sterilized. Terminal sterilization involves the product being sealed in its container & then sterilized usually by heat, by ionizing radiation or less commonly by ethylene oxide. Such products are produced in clean areas A product that can not be terminally sterilized is prepared aseptically from previously sterilized material or by sterile filtration & then filled in sterile containers. Strict aseptic conditions are required. Figure 23.2 ٧
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Clean & aseptic areas Design of premises Sterile production should be carried in separate units from other manufacturing areas. Internal surfaces, fittings and equipment Particulate µbial contamination must be prevented, therefore (all surfaces) walls, ceilings and floors should possess smooth, impervious surfaces which will: (i) prevent the accumulation of dust or other particulate matter; and (ii) allow for easy and repeated cleaning and disinfection. Surfaces are usually from plastic or epoxy-coated plaster. Coving must be used, windows should be flushed with the walls & not openable. Cupboards, drawers etc should be kept to minimum & preferably made from stainless steel or plastic. All equipment must be easily cleaned & sterilized or disinfected. Services Adequate illumination, lights housed in false ceiling, sockets switches must be flush with the wall. Sinks should be of stainless steel, drains avoided if possible. Sinks & drains should be excluded from aseptic areas ١٠
Air supply Areas for the manufacture of sterile products are classified according to the required characteristics of the environment, 4 grades are defined based on airborne contamination. Thus, air supplied influences environmental quality. Tables below show max permitted number of particles (Viable & non viable /ft 3 Table 1 or /m 3 Table 2 ) Table 1 ١١
Table 2 ١٢
Filtered air is used to achieve the necessary standards; this should be maintained at positive pressure throughout a clean or aseptic area, with the highest pressure in the most critical rooms (aseptic or clean filling rooms) and a progressive reduction through the preparation and changing rooms Additional protection in both the filling area of the clean room and in the aseptic unit is needed. This is provided by a protective work station supplied with a unidirectional flow of filtered sterile air (thru HEPA filters) known as a laminar airflow unit in which the displacement of air is either horizontal (i.e. from back to front) or vertical (i.e. from top to bottom). Thus, airborne contamination is not added to the work space and any generated by manipulations within that area is swept away by the laminar air currents. Clothing Clothing must be of non-shedding fibers. Trouser suits, close fitting at the neck, wrists & ankles are worn. Clean suits should be provided once a day, fresh head wear, overshoes & powder free gloves should be provided every working session. Special laundering facilities is needed. ١٣
١٤ Changing facilities (Fig 23.4). Entry to aseptic area should be through changing room fitted with interlocking doors (airlock) for personnel use only. Entry should be from black to grey area via step-over sill, to the white area (the highest level of cleanliness). In grey area, the sink fitted with elbow or foot operated taps.
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Cleaning and disinfection A strict cleaning and disinfection policy is essential. Rotation of different disinfectants reduces the risk of resistance. In-use dilution must not be stored unless sterile. Disinfectants & detergents for grade A & B areas must be sterile. Daily cleaning & disinfection for floors& horizontal surfaces; walls & ceiling periodically not exceeding 1 month. Operation Number of persons involved in sterile manufacturing should be kept to minimum to avoid turbulence & shedding of particles & organism. Avoid excessive activity to reduce turbulence &shedding. Ingredients going to clean areas must be transferred to suitable metal or plastic containers. Containers & closures for terminal sterilization should be cleaned & finally washed with apyrogenic water before use. While those for aseptic filling, in addition should be sterilized after washing & rinsing. ١٨